EP3639829B1 - Use of isovalerylspiramycin i or iii in preparation of drug for treating and/or preventing tumour, and drug - Google Patents
Use of isovalerylspiramycin i or iii in preparation of drug for treating and/or preventing tumour, and drug Download PDFInfo
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- EP3639829B1 EP3639829B1 EP18827765.1A EP18827765A EP3639829B1 EP 3639829 B1 EP3639829 B1 EP 3639829B1 EP 18827765 A EP18827765 A EP 18827765A EP 3639829 B1 EP3639829 B1 EP 3639829B1
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- tumor
- isovaleryl spiramycin
- iii
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Definitions
- the present disclosure belongs to the technical field of pharmaceuticals, and specifically relates to isovaleryl spiramycin I or III for use in the treatment or prevention of a tumor.
- Tumor is a common and frequently-occurring disease, and refers to the neoformation or neoplasm formed by clonal abnormal proliferation and differentiation caused by genetic mutation and loss of normal regulation of growth and differentiation of the histocyte of the organism under the long-term action of tumorigenic factors in vivo and in vitro.
- Tumors are classified into benign tumors and malignant tumors.
- the malignant tumors are further divided into three types: carcinomas derived from epithelial tissues, sarcomas derived from mesenchymal tissues, and carcinosarcomas.
- carcinomas derived from epithelial tissues sarcomas derived from mesenchymal tissues
- carcinosarcomas carcinosarcomas.
- carcinomas derived from epithelial tissues sarcomas derived from mesenchymal tissues
- carcinosarcomas carcinosarcomas.
- carcinomas derived from epithelial tissues sarcomas
- the malignant tumors are one of the major malignant diseases threatening human health and the first cause of death of the world's population. According to the latest statistics, in 2007, about 7.9 million people in the world died of various cancers, accounting for 13% of all deaths, and more than 12 million cancer cases were diagnosed, wherein 72% or more of tumor patients and deaths have occurred in underdeveloped countries, and it is rising continuously. In 2015, 9 million people in the world died of tumors, and it is expected that more than 12 million people will die of tumors in 2030. At present, the annual number of cancer cases in China is about 2.8 million, and the number of cancer deaths is more than 400,000, ranking first among all kinds of diseases in China, and showing a rising trend.
- European patent application number EP3607952A1 describes the use of carrimycin and pharmaceutically acceptable salts thereof for the preparation of a medicament for the treatment of tumors.
- PCT patent publication number WO2007/144876A1 describes the use of a macrolide antibiotic for the manufacture of a medicament for the treatment or prevention of a particular cancer.
- European patent application number EP2578596A1 describes the preparation, use and pharmaceutical compositions or levocarrimycin.
- Chinese patent application number CN101785778A describes the separation of an antibiotic comprising isovaleryl-spiramycin I and the application of the antibiotic in resistant infectious diseases.
- Carrimycin is a new type of antibiotic with the 4"- isovaleryl spiramycin as a main component, and carrimycin is formed by cloning the 4"-o-acyl-transferase of the carbomycin producing strain into a spiramycin producing strain by a transgenic technology, directionally acylating spiramycin 4"-OH, and adding an isovaleryl side chain at the 4"-position.
- Carrimycin is composed of a variety of spiramycin derivatives with the main active component isovaleryl spiramycin (I+II+III) having a total content of no less than 60%, and is a pharmaceutically acceptable pharmaceutical composition.
- the central structure of the main component of the carrimycin is a 16-membered lactone ring, and the 16-membered lactone ring links one molecule of forosamine, one molecule of mycaminose and one molecule of mycarose.
- Its main component isovaleryl spiramycin I, II, III differs from the spiramycin structure in that the group connected to the 4'-position of mycarose is isovaleryl rather than hydroxyl.
- the drug is jointly declared by Tonglian Shengyang Group as the 1.1 type of new drug.
- Carrimycin and macrolide antibiotics have many commonalities due to their similar chemical structures: they are easily soluble in most organic solvents such as esters, acetone, chloroform, alcohols, etc., slightly soluble in petroleum ether, and insoluble in water. Due to the presence of two dimethylamine groups in the molecular structure, carrimycin is alkalescence and easily soluble in an acidic aqueous solution.
- Carrimycin has a "negative solubility" property in which the solubility decreases with an increase temperature. Since isovaleryl spiramycin, the main component of carrimycin, has a longer carbon chain at the 4"-position and a poor hydrophilicity, the solubility of carrimycin in water is smaller than that of spiramycin and 4"-acetylspiramycin.
- Carrimycin is a white amorphous powder with slight hygroscopicity, and specific rotation of about -80.8°, maximum ultraviolet absorption wavelength of 231-232 nm.
- Carrimycin contains weak fluorescent chromophores, presents a purple reaction producing a strong purple fluorescence in case of concentrated sulfuric acid or hydrochloric acid, and has a maximum absorbance at 231-232 nm.
- the drug has good lipophilicity, strong tissue penetration ability, rapid oral absorption, long body maintenance time, and sustained post antibiotic effects.
- macrolide antibiotics According to a relationship between pharmacodynamics and chemical conformation, after the 4"-position of the macrolide antibiotics acylation, macrolide antibiotics have improved lipophilicity and in vivo activity, and significantly improved in vivo antibacterial activity and clinical therapeutic effects, and the in vivo stability of antibiotics enhances with the growing of the carbon chain of the 4"-hydroxy ester, that is, isovaleryl spiramycin > butyryl spiramycin > propionyl spiramycin > acetyl spiramycin.
- the preliminary in vitro and in vivo pharmacodynamic tests showed that the drug not only has good antibacterial activity against most G + bacteria, but also has certain effects on some G - bacteria, and its technical indicators are obviously superior to those of azithromycin, erythromycin, acetyl spiramycin, and medemycin.
- erythromycin resistant bacteria gonococcus, pneumococcus, staphylococcus aureus, bacillus pyocyaneus, bacillus influenzae, haemophilus influenzae, bacteroides fragilis, legionella, multi-line bacillus and clostridium perfringens, and a tiny cross resistance against staphylococcus aureus with clinical resistance to the erythromycin.
- Carrimycin will be primarily used to treat gram-positive infections, especially upper respiratory tract infections, and may be used for urinary tract infections.
- the technical problem to be solved by the present disclosure is to overcome the defects of the prior art and provide use of isovaleryl spiramycin I or III in manufacturing medicament for treating and/or preventing tumor.
- the present disclosure firstly provides use of isovaleryl spiramycin I or III in manufacturing medicament for the treating and/or preventing tumor.
- the tumor includes solid tumor and non-solid tumor.
- the solid tumor includes benign solid tumor and malignant solid tumor; the non-solid tumor is lymphoma or leukemia.
- the malignant solid tumor is breast cancer, liver cancer, lung cancer, renal cancer, brain tumor, cervical cancer, prostate cancer, lymphoma, pancreatic cancer, esophageal cancer, gastric cancer, colon cancer, thyroid cancer, bladder cancer, or malignant skin tumor;
- the brain tumor is glioma or meningioma
- the gastric cancer is gastric adenocarcinoma.
- the present disclosure shows by experiments that isovaleryl spiramycin I, II and/or III show good antiproliferative activity on human breast cancer cells MCF-7 and MDA-MB-231, human hepatoma cells HepG2, human non-small cell lung cancer cells A549, human large cell lung cancer cells H460 and H1299, human renal clear cell adenocarcinoma cell 786-O, human renal cell adenocarcinoma cell 769-P, human tissue lymphoma cell U937, human cervical cancer cell HeLa, human prostate cancer cell PC3, human glioma cell U251, human glioblastoma cell A172, human pancreatic cancer cell PANC-1, human colon cancer cell HT-29, human esophageal cancer cell TE-1, human gastric adenocarcinoma cell SGC7901, human promyelocytic leukemia cell HL-60, human thyroid cancer cell TPC-1, and human bladder cancer cell T-24, confirming that isovaleryl spir
- the medicament is in various formulations made of isovaleryl spiramycin I or III and pharmaceutically acceptable salts of isovaleryl spiramycin I or III and pharmaceutically acceptable adjuvants.
- the medicament is in various formulations made of isovaleryl spiramycin I or III and the pharmaceutically acceptable salts of isovaleryl spiramycin I or III and anti-tumor drugs and the pharmaceutically acceptable adjuvants.
- the isovaleryl spiramycin I, or III and at least one of the anti-tumor drugs can be formulated into a compound preparation.
- the dosage ratio of isovaleryl spiramycin I or III to a second active component is 1-99: 99-1, preferably 5-95:95-5, more preferably 10-90:90-10, further preferably 20-80:80-20.
- the medicament is a combination of a first agent and a second agent
- the first agent contains isovaleryl spiramycin I, or III and the pharmaceutically acceptable salts of isovaleryl spiramycin I, or III
- the second agent contains an anti-tumor drug.
- the first agent containing the active component isovaleryl spiramycin I, or III can be used together with the second agent containing one or more than one drug selected from a group containing a chemotherapy drug, a radiotherapy drug, a targeted therapy drug or an immunotherapeutic drug.
- the first agent and the second agent can be administered in no particular order, namely, the first agent may be used first, or the second agent may be used first, or both are used simultaneously.
- the dosage ratio of the first agent to the second agent is 1-99: 99-1, preferably 5-95:95-5, more preferably 10-90:90-10, further preferably 20-80:80-20.
- the anti-tumor drug is a chemotherapy drug, a radiotherapy drug, a targeted therapy drug, and/or an immunotherapeutic drug.
- the present disclosure also provides a medicament for treating and/or preventing tumor, the active component of the medicament includes isovaleryl spiramycin I, or III.
- the medicament also includes a second active component.
- the second active component includes one or more than one drug selected from a group containing a chemotherapy drug, a radiotherapy drug, a targeted therapy drug and an immunotherapeutic drug.
- the present disclosure also provides a combination product for treating and/or preventing tumor, the combination product includes a first agent and a second agent, and the active component of the first agent is isovaleryl spiramycin I or III and the second agent includes one or more than one drug selected from a group containing a chemotherapy drug, a radiotherapy drug, a targeted therapy drug and an immunotherapeutic drug.
- the medicament or the first agent is a pharmaceutically acceptable formulation.
- a dose of isovaleryl spiramycin I, or III in the medicament or the first agent is in a range from 5 to 1,500 mg; preferably in a range from 50 to 1,000 mg; more preferably in a range from 100 to 400 mg.
- isovaleryl spiramycin I can be separated and prepared according to the methods of the prior art, such as the isovaleryl spiramycin I can be separated and prepared according to a method of Example 1 in CN101785778A .
- Isovaleryl spiramycin II can be separated and prepared according to the methods of the prior art, such as the isovaleryl spiramycin II can be separated and prepared according to a method of Example 1 in CN101785779A .
- Isovaleryl spiramycin III can be separated and prepared according to the methods of the prior art, such as the isovaleryl spiramycin III can be separated and prepared according to a method of Example 1 in CN101773510A .
- the present disclosure shows that isovaleryl spiramycin I, or III have good anti-tumor effects, especially have good curative effects on tumors including breast cancer, liver cancer, lung cancer, lymphoma, cervical cancer, prostate cancer, colon cancer or leukemia.
- the present disclosure not only provides a theoretical basis for the application and clinical promotion of isovaleryl spiramycin I, or III in the preparation of drugs for treating and/or preventing tumor, but also has important economic and social benefits.
- the main drug and adjuvants respectively were made to pass through a 100-mesh sieve, and a prescription amount of isovaleryl spiramycin I, a prescription amount of microcrystalline cellulose and a 1/2 prescription amount of sodium carboxymethyl starch were uniformly mixed, and then a 5% povidone K 30 aqueous solution was added to make a soft material.
- a 18-mesh sieve was used for granulating, and the wet granules were dried under a ventilated condition at 60°C for 2 hours.
- a 18-mesh sieve was used for dispersing the granules, and then a 1/2 prescription amount of sodium carboxymethyl starch and prescription amount of magnesium stearate were added. And after the materials were uniformly mixed, the mixture was tabletted with a shallow concave stamping die having a diameter of 11 mm to obtain a tablet core containing drugs, wherein the tablet is 350 mg in weight and 6.5 kg in hardness.
- the required Opadry II (white) was weighed, the required amount of water was added into a liquid preparation container, the Opadry II was added into the liquid preparation container in batch. After all the Opadry II was added, the stirring speed was reduced to make the spiral disappear, and then stirring was continued to be performed for 30min to obtain the coating liquid.
- the tablet core was placed in a coating pan, the coating conditions were determined, and coating was carried out with the host speed of 20 r/min, the inlet air temperature of 40°C, the outlet air temperature of 30°C, the spray pressure of 0.02 Mpa, and the spray slurry flow rate of 1ml/min. And after a constant state was achieved, the coating was continuously to be sprayed for 1.5 hours until the surfaces of the tablets were smooth and uniform in color, wherein tablets which were in compliance with the inspection standard of film coatings were qualified. The coating gains about 5% in weight.
- Preparation process an appropriate amount of starch was weighed, diluted to a concentration of 15%, and heated to a paste to get a binder; the main material isovaleryl spiramycin I, and the adjuvants starch, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, and magnesium stearate pass through a 100-mesh sieve, respectively, and the required main material and adjuvants were weighed according to the prescription amount.
- the starch paste with a starch concentration of 15% was used to prepare the mixture into a soft material which was granulated by a 14-mesh sieve, and granules were dried at 50-60°C to control a water content to be 3-5%.
- a 14-mesh sieve was used for dispersing the granules, and then sodium carboxymethyl starch and magnesium stearate were added to be mixed, and the granule content was measured.
- the weight of the tablet was calculated according to the granule content, and the mixture was tabletted (with a ⁇ 9 mm shallow concave punch), then the difference in the weight of the tablets was detected. After passing the test, the tablets were packaged.
- Preparation process the main material isovaleryl spiramycin I and the adjuvant medicinal starch were separately weighed according to the process formula amount, and then fully mixed in a mixer for 1.5-2 hours.
- the data obtained by sampling and content testing should be basically consistent with the theoretical data (the weight of each capsule was about 0.105g), and the qualified No.
- Preparation process the isovaleryl spiramycin I raw powder, citric acid and sucrose were respectively grinded into granules by a high-speed jet mill, and 85% of the granules pass through a 300-mesh sieve, 15% of the granules pass through a 180-mesh sieve. Then the fine powder after grinding was weighed according to the prescription amount and fully mixed for 1-1.5 hours, the content was measured, the loading capacity was calculated (the theoretical loading capacity is 500mg per bag). Then the mixture was put into a bagging machine, aluminum foil paper was installed, and filling was carried out according to the operation requirements of a filling machine. The difference was allowed to be within ⁇ 5 %, and after the filling, the outer packaging was carried out after passing the inspection.
- Preparation process the isovaleryl spiramycin I raw powder, powdered sugar and dextrin were made to pass through a 120-mesh sieve, and the isovaleryl spiramycin I, powdered sugar and dextrin were weighed according to the prescription amount and uniformly mixed. And the above uniformly mixed materials were made into a soft material with a 5% PV-P-K 30 mucilage, and then the soft material was granulated with a swinging granulation machine, dried at 70°C and subjected to granule dispersion, and the resulting granules were subpackaged after being qualified for inspection.
- Preparation Process Preparation of the tablet core: the main drug and adjuvants respectively were made to pass through a 100-mesh sieve, and a prescription amount of isovaleryl spiramycin II, a prescription amount of microcrystalline cellulose and a 1/2 prescription amount of sodium carboxymethyl starch were uniformly mixed, and then a 5% povidone K 30 aqueous solution was added to make a soft material. A 18-mesh sieve was used for granulating, and the wet granules were dried under a ventilated condition at 60°C for 2 hours.
- a 18-mesh sieve was used for dispersing the granules, and then a 1/2 prescription amount of sodium carboxymethyl starch and prescription amount of magnesium stearate were added. And after the materials were uniformly mixed, the mixture was tabletted with a shallow concave stamping die having a diameter of 11 mm to obtain a tablet core containing drugs, wherein the tablet is 350 mg in weight and 6.5 kg in hardness.
- the required Opadry II (white) was weighed, the required amount of water was added into a liquid preparation container, the Opadry II was added into the liquid preparation container in batch. After all the Opadry II was added, the stirring speed was reduced to make the spiral disappear, and then stirring was continued to be performed for 30min to obtain the coating liquid.
- the tablet core was placed in a coating pan, the coating conditions were determined, and coating was carried out with the host speed of 20 r/min, the inlet air temperature of 40°C, the outlet air temperature of 30°C, the spray pressure of 0.02 Mpa, and the spray slurry flow rate of 1ml/min. And after a constant state was achieved, the coating was continuously to be sprayed for 1.5 hours until the surfaces of the tablets were smooth and uniform in color, wherein tablets which were in compliance with the inspection standard of film coatings were qualified. The coating gains about 5% in weight.
- Preparation process an appropriate amount of starch was weighed, diluted to a concentration of 15%, and heated to a paste to make a binder.
- the main material isovaleryl spiramycin II, and the adjuvants starch, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, and magnesium stearate were made to pass through a 100-mesh sieve, respectively, and the required main material and adjuvants were weighed according to the prescription amount.
- the starch paste with a starch concentration of 15% was used to prepare the mixture into a soft material which was granulated by a 14-mesh sieve, and granules were dried at 50-60°C to control a water content to be 3-5%.
- a 14-mesh sieve was used for dispersing the granules, and then sodium carboxymethyl starch and magnesium stearate were added to be mixed, and the granule content was measured.
- the weight of the tablet was calculated according to the granule content, and the mixture was tabletted (with a ⁇ 9 mm shallow concave punch), then the difference in the weight of the tablets was detected. After passing the test, the tablets were packaged.
- Preparation process the main material isovaleryl spiramycin II and the adjuvant medicinal starch were separately weighed according to the process formula amount, and then fully mixed in a mixer for 1.5-2 hours.
- the data obtained by sampling and content testing should be basically consistent with the theoretical data (the weight of each capsule was about 0.105g), and the qualified No.
- Preparation process the isovaleryl spiramycin II raw powder, citric acid and sucrose were respectively grinded into granules by a high-speed jet mill, and 85% of the granules pass through a 300-mesh sieve, 15% of the granules pass through a 180-mesh sieve. Then the fine powder after grinding was weighed according to the prescription amount and fully mixed for 1-1.5 hours, the content was measured, the loading capacity was calculated (the theoretical loading capacity was 500mg per bag). Then the mixture was put into a bagging machine, aluminum foil paper was installed, and filling was carried out according to the operation requirements of a filling machine. The difference was allowed to be within ⁇ 5 %, and after the filling, the outer packaging was carried out after passing the inspection.
- Preparation process the isovaleryl spiramycin II raw powder, powdered sugar and dextrin were made to pass through a 120-mesh sieve, and the isovaleryl spiramycin II, powdered sugar and dextrin were weighed according to the prescription amount and uniformly mixed.
- the above uniformly mixed materials were made into a soft material with a 5% PV-P-K 30 mucilage, and then the soft material was granulated with a swinging granulation machine, dried at 70°C and subjected to granule dispersion, and the resulting granules were subpackaged after being qualified for inspection.
- Preparation Process Preparation of the tablet core: the main drug and adjuvants respectively were made to pass through a 100-mesh sieve, and a prescription amount of isovaleryl spiramycin III, a prescription amount of microcrystalline cellulose and a 1/2 prescription amount of sodium carboxymethyl starch were uniformly mixed, and then a 5% povidone K 30 aqueous solution was added to make a soft material. A 18-mesh sieve was used for granulating, and the wet granules were dried under a ventilated condition at 60°C for 2 hours.
- a 18-mesh sieve was used for dispersing the granules, and then a 1/2 prescription amount of sodium carboxymethyl starch and prescription amount of magnesium stearate were added. And after the materials were uniformly mixed, the mixture was tabletted compressed with a shallow concave stamping die having a diameter of 11 mm to obtain a tablet core containing drugs, wherein the tablet is 350 mg in weight and 6.5 kg in hardness.
- the required Opadry II (white) was weighed, the required amount of water was added into a liquid preparation container, the Opadry II was added into the liquid preparation container in batch. After all the Opadry II was added, the stirring speed was reduced to make the spiral disappear, and then stirring was continued to be performed for 30min to obtain the coating liquid.
- the tablet core was placed in a coating pan, the coating conditions were determined, and coating was carried out with the host speed of 20 r/min, the inlet air temperature of 40°C, the outlet air temperature of 30°C, the spray pressure of 0.02 Mpa, and the spray slurry flow rate of 1ml/min. And after a constant state was achieved, the coating was continuously to be sprayed for 1.5 hours until the surfaces of the tablets were smooth and uniform in color, wherein tablets which were in compliance with the inspection standard of film coatings were qualified. The coating gains about 5% in weight.
- Preparation process an appropriate amount of starch was weighed, diluted to a concentration of 15%, and heated to a paste to get a binder.
- the main material isovaleryl spiramycin III, and the adjuvants starch, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, and magnesium stearate were made to pass through a 100-mesh sieve, respectively, and the required main material and adjuvants were weighed according to the prescription amount.
- the starch paste with a starch concentration of 15% was used to prepare the mixture into a soft material which was granulated by a 14-mesh sieve, and granules were dried at 50-60°C to control a water content to be 3-5%.
- a 14-mesh sieve was used for dispersing the granules, and then sodium carboxymethyl starch and magnesium stearate were added to be mixed, and the granule content was measured;.
- the weight of the tablet was calculated according to the granule content, and the mixture was tabletted (with a ⁇ 9 mm shallow concave punch), then the difference in the weight of the tablets was detected. After passing the test, the tablets were packaged.
- Preparation process the main material isovaleryl spiramycin III and the adjuvant medicinal starch were separately weighed according to the process formula amount, and then fully mixed in a mixer for 1.5-2 hours.
- the data obtained by sampling and content testing should be basically consistent with the theoretical data (the weight of each capsule was about 0.105g), and the qualified No.
- Preparation process the isovaleryl spiramycin III raw powder, citric acid and sucrose were respectively grinded into granules by a high-speed jet mill, and 85% of the granules pass through a 300-mesh sieve, 15% of the granules pass through a 180-mesh sieve. And then the fine powder after grinding was weighed according to the prescription amount and fully mixed for 1-1.5 hours, the content was measured, the loading capacity was calculated (the theoretical loading capacity was 500mg per bag). Then the mixture was put into a bagging machine, aluminum foil paper was installed, and filling was carried out according to the operation requirements of a filling machine. The difference was allowed to be within ⁇ 5 %, and after the filling, the outer packaging was carried out after passing the inspection.
- Preparation process the isovaleryl spiramycin III raw powder, powdered sugar and dextrin were made to pass through a 120-mesh sieve, and the isovaleryl spiramycin III, powdered sugar and dextrin were weighed according to the prescription amount and uniformly mixed.
- the above uniformly mixed materials were made into a soft material with a 5% PV-P-K 30 mucilage, and then the soft material was granulated with a swinging granulation machine, dried at 70°C and subjected to granule dispersion, and the resulting granules were subpackaged after being qualified for inspection.
- 500 mg of isovaleryl spiramycin III raw powder was uniformly mixed with an equimolar amount of adipic acid, and the mixture was dissolved in 5 ml of water to obtain a faint yellow clear solution having a pH between 4.6 and 5.6. Further, 40 mg of mannitol was added as a lyophilized proppant into the faint yellow clear solution, and after being frozen rapidly at a low temperature for 9 hours, the material was freeze-dried to obtain a faint yellow loose mass, which was dissolved in 10 ml of sterile water before being used.
- the purpose of the assay is to evaluate the in vitro cell proliferation inhibition or cytotoxic activity of a tested sample.
- Cell strains Human breast cancer cells MCF-7 and MDA-MB-231, human hepatoma cells HepG2, human non-small cell lung cancer cells A549, human large cell lung cancer cells H460 and H1299, human renal clear cell adenocarcinoma cell 786-O, human renal cell adenocarcinoma cell 769-P, human glioma cell U251, human glioblastoma cell A172, human tissue lymphoma cell U937, human cervical cancer cell HeLa, human prostate cancer cell PC3, human pancreatic cancer cell PANC-1, human esophageal cancer cell TE-1, human gastric adenocarcinoma cell SGC7901, human colon cancer cell HT-29, human promyelocytic leukemia cell HL-60, human thyroid cancer cell TPC-1, and human bladder cancer cell T-24.
- Reagents RPMI1640 medium, MEM medium, DMEM low sugar medium, fetal calf serum purchased from Gibco, USA, trypsin, glutamine, penicillin, streptomycin, dimethyl sulfoxide (DMSO), and methyl-thiazol-tetrazolium (MTT) purchased from Sigma, USA.
- Tumor cell growth inhibition rate % A 492 negative control ⁇ A 492 dosing group / A 492 negative control ⁇ 100 %
- results The evaluation results of in vitro antiproliferative activity of the samples selected from human breast cancer cells MCF-7 and MDA-MB-231, human hepatoma cells HepG2, human non-small cell lung cancer cells A549, human large cell lung cancer cells H460 and H1299, human renal clear cell adenocarcinoma cell 786-O, human renal cell adenocarcinoma cell 769-P, human glioma cell U251, human glioblastoma cell A172, human tissue lymphoma cell U937, human cervical cancer cell HeLa, human prostate cancer cell PC3, human pancreatic cancer cell PANC-1, human esophageal cancer cell TE-1, human gastric adenocarcinoma cell SGC7901, human colon cancer cell HT-29, human promyelocytic leukemia cell HL-60, human thyroid cancer cell TPC-1, and human bladder cancer cell T-24 are shown in Table 1, Table 2 and Table 3: Table 1.
- H460 cells in a logarithmic growth phase were taken and subjected to a trypan blue exclusion experiment showing that the cell viability was more than 95%, then the cells were subjected to trypsinization, centrifugation, and supernatant removal. Then cell concentration was adjusted to 1 ⁇ 10 7 /ml with matrigel, then each nude mouse was inoculated subcutaneously with 0.2ml of cells at its right armpit and recorded as the first day of inoculation.
- mice When the tumor grows to be greater than or equal to 100 mm 3 , the mice were randomly divided into 11 groups with 6 mice in each group: isovaleryl spiramycin I groups with doses of 25, 50 and 100 mg/kg, isovaleryl spiramycin II groups with doses of 25, 50 and 100 mg/kg, and isovaleryl spiramycin III groups with doses of 25, 50 and 100 mg/kg. Each group was continuously administered intragastrically for 30 days with a dose of 20 ml/kg. The mice were sacrificed the next day after drug withdrawal and the indicators were tested. The long diameter and short diameter of the tumor, and the body weight of each mouse were recorded every 3 days from drug administration to nude mouse sacrifice.
- Tumor growth inhibition rate (%) (1-the average tumor weight of the treatment group/ the average tumor weight of the model group) ⁇ 100%.
- test results show that compared with the control group, each drug-administered group has a certain degree of inhibition on the tumor growth inhibition rate, tumor volume, relative tumor volume and relative tumor proliferation rate (see Table 4, and Table 5).
- the tumor growth inhibition rates of isovaleryl spiramycin I groups with low, medium and high doses are 20.70%, 46.33% and 70.11%, respectively.
- the tumor growth inhibition rates of isovaleryl spiramycin II groups with low, medium and high doses are 14.22%, 34.43% and 61.12%, respectively.
- the tumor growth inhibition rates of isovaleryl spiramycin III groups with low, medium and high doses are 17.41%, 23.31% and 63.93%, respectively.
- the tumor volume and relative tumor volume of isovaleryl spiramycin I, II and III groups with low, medium and high doses are significantly lower than those of the model group (P ⁇ 0.05).
- the relative tumor proliferation rates of isovaleryl spiramycin I groups with low, medium and high doses are 56.56%, 49.00% and 31.96% respectively.
- the relative tumor proliferation rates of isovaleryl spiramycin II groups with low, medium and high doses are 51.97%, 46.49% and 37.89% respectively.
- the relative tumor proliferation rates of isovaleryl spiramycin III groups with low, medium and high doses are 63.03%, 42.54% and 35.95% respectively.
- H1299 cells in a logarithmic growth phase were taken and subjected to a trypan blue exclusion experiment showing that the cell viability was more than95%, then the cells were subjected to trypsinization, centrifugation, and supernatant removal. Then cell concentration was adjusted to 1 ⁇ 10 7 /ml with matrigel, then each nude mouse was inoculated subcutaneously with 0.2ml of cells at its right armpit and recorded as the first day of inoculation.
- mice When the tumor grows to be greater than or equal to 100 mm 3 , the mice were randomly divided into 11 groups with 6 mice in each group: isovaleryl spiramycin I groups with doses of 25, 50 and 100 mg/kg, isovaleryl spiramycin II groups with doses of 25, 50 and 100 mg/kg, and isovaleryl spiramycin III groups with doses of 25, 50 and 100 mg/kg. Each group was continuously administered intragastrically for 30 days with a dose of 20 ml/kg. The mice were sacrificed the next day after drug withdrawal and the indicators were tested. The long diameter and short diameter of the tumor, and the body weight of each mouse were recorded every 3 days from drug administration to nude mouse sacrifice.
- Tumor growth inhibition rate (%) (1-the average tumor weight of the treatment group/ the average tumor weight of the model group) ⁇ 100%.
- each drug-administered group has a certain degree of inhibition on the tumor growth inhibition rate, tumor volume, relative tumor volume and relative tumor proliferation rate (see Table 6, and Table 7).
- the tumor growth inhibition rates of isovaleryl spiramycin I groups with low, medium and high doses are 22.11%, 43.83% and 69.95%, respectively.
- the tumor growth inhibition rates of isovaleryl spiramycin II groups with low, medium and high doses are 17.32%, 44.21% and 58.37%, respectively.
- the tumor growth inhibition rates of isovaleryl spiramycin III groups with low, medium and high doses are 13.11%, 49.38% and 62.78%, respectively.
- the tumor volume and relative tumor volume of isovaleryl spiramycin I, II and III groups with low, medium and high doses are significantly lower than those of the model group (P ⁇ 0.05).
- the relative tumor proliferation rates of isovaleryl spiramycin I groups with low, medium and high doses are 89.42%, 49.81% and 27.43% respectively.
- the relative tumor proliferation rates of isovaleryl spiramycin II groups with low, medium and high doses are 83.01%, 46.94% and 36.86% respectively.
- the relative tumor proliferation rates of isovaleryl spiramycin III groups with low, medium and high doses are 89.88%, 48.11% and 32.43% respectively.
- TE-1 cells in a logarithmic growth phase were taken and subjected to a trypan blue exclusion experiment showing that the cell viability was more than 95%, then the cells were subjected to trypsinization, centrifugation, and supernatant removal. Then cell concentration was adjusted to 1 ⁇ 10 7 /ml with matrigel, then each nude mouse was inoculated subcutaneously with 0.2ml of cells at its right armpit and recorded as the first day of inoculation.
- mice When the tumor grows to be greater than or equal to 100 mm 3 , the mice were randomly divided into 11 groups with 6 mice in each group: a model group, a cyclophosphamide group, isovaleryl spiramycin I groups with doses of 25, 50 and 100 mg/kg, isovaleryl spiramycin II groups with doses of 25, 50 and 100 mg/kg, and isovaleryl spiramycin III groups with doses of 25, 50 and 100 mg/kg. Each group was continuously administered intragastrically for 30 days with a dose of 20 ml/kg. The mice were sacrificed the next day after drug withdrawal and the indicators were tested. The long diameter and short diameter of the tumor, and the body weight of each mouse were recorded every 3 days from drug administration to nude mouse sacrifice.
- Tumor growth inhibition rate (%) (1-the average tumor weight of the treatment group/ the average tumor weight of the model group) ⁇ 100%.
- each drug-administered group has a certain degree of inhibition on the tumor growth inhibition rate, tumor volume, relative tumor volume and relative tumor proliferation rate (see Table 8, and Table 9).
- the tumor growth inhibition rates of isovaleryl spiramycin I groups with low, medium and high doses are 30.92%, 51.01% and 69.71%, respectively.
- the tumor growth inhibition rates of isovaleryl spiramycin II groups with low, medium and high doses are 24.87%, 43.78% and 72.48%, respectively.
- the tumor growth inhibition rates of isovaleryl spiramycin III groups with low, medium and high doses are 22.64%, 40.17% and 65.46%, respectively.
- the tumor volume and relative tumor volume of isovaleryl spiramycin I, II and III groups with low, medium and high doses are significantly lower than those of the model group (P ⁇ 0.05).
- the relative tumor proliferation rates of isovaleryl spiramycin I groups with low, medium and high doses are 60.55%, 40.70% and 20.61% respectively.
- the relative tumor proliferation rates of isovaleryl spiramycin II groups with low, medium and high doses are 70.32%, 50.51% and 36.49% respectively.
- the relative tumor proliferation rates of isovaleryl spiramycin III groups with low, medium and high doses are 66.52%, 50.71% and 30.72% respectively.
- SGC7901 cells in a logarithmic growth phase were taken and subjected to a trypan blue exclusion experiment showing that the cell viability is was more than 95%, then the cells were subjected to trypsinization, centrifugation, and supernatant removal. Then cell concentration was adjusted to 1 ⁇ 10 7 /ml with matrigel, then each nude mouse was inoculated subcutaneously with 0.2ml of cells at its right armpit and recorded as the first day of inoculation.
- mice When the tumor grows to be greater than or equal to 100 mm 3 , the mice were randomly divided into 11 groups with 6 mice in each group: a model group, a cyclophosphamide group, isovaleryl spiramycin I groups with doses of 25, 50 and 100 mg/kg, isovaleryl spiramycin II groups with doses of 25, 50 and 100 mg/kg, and isovaleryl spiramycin III groups with doses of 25, 50 and 100 mg/kg. Each group was continuously administered intragastrically for 30 days with a dose of 20 ml/kg. The mice were sacrificed the next day after drug withdrawal and the indicators were tested. The long diameter and short diameter of the tumor, and the body weight of each mouse were recorded every 3 days from drug administration to nude mouse sacrifice.
- Tumor growth inhibition rate (%) (1-the average tumor weight of the treatment group/ the average tumor weight of the model group) ⁇ 100%.
- each drug-administered group has a certain degree of inhibition on the tumor growth inhibition rate, tumor volume, relative tumor volume and relative tumor proliferation rate (see Table 10, and Table 11).
- the tumor growth inhibition rates of isovaleryl spiramycin I groups with low, medium and high doses are 31.56%, 53.13% and 70.78%, respectively.
- the tumor growth inhibition rates of isovaleryl spiramycin II groups with low, medium and high doses are 24.44%, 41.76% and 70.24%, respectively.
- the tumor growth inhibition rates of isovaleryl spiramycin III groups with low, medium and high doses are 21.68%, 41.13% and 63.34%, respectively.
- the tumor volume and relative tumor volume of isovaleryl spiramycin I, II and III groups with low, medium and high doses are significantly lower than those of the model group (P ⁇ 0.05).
- the relative tumor proliferation rates of isovaleryl spiramycin I groups with low, medium and high doses are 61.13%, 42.67% and 20.23% respectively.
- the relative tumor proliferation rates of isovaleryl spiramycin II groups with low, medium and high doses are 70.48%, 51.42% and 36.95% respectively.
- the relative tumor proliferation rates of isovaleryl spiramycin III groups with low, medium and high doses are 65.48%, 49.44% and 30.34% respectively.
- PC3 cells in a logarithmic growth phase were taken and subjected to a trypan blue exclusion experiment showing that the cell viability was more than 95%, then the cells were subjected to trypsinization, centrifugation, and supernatant removal. Then cell concentration was adjusted to 1 ⁇ 10 7 /ml with matrigel, then each nude mouse was inoculated subcutaneously with 0.2ml of cells at its right armpit and recorded as the first day of inoculation.
- mice When the tumor grows to be greater than or equal to 100 mm 3 , the mice were randomly divided into 11 groups with 6 mice in each group: a model group, a cyclophosphamide group, isovaleryl spiramycin I groups with doses of 25, 50 and 100 mg/kg, isovaleryl spiramycin II groups with doses of 25, 50 and 100 mg/kg, and isovaleryl spiramycin III groups with doses of 25, 50 and 100 mg/kg. Each group was continuously administered intragastrically for 30 days with a dose of 20 ml/kg. The mice were sacrificed the next day after drug withdrawal and the indicators were tested. The long diameter and short diameter of the tumor, and the body weight of each mouse were recorded every 3 days from drug administration to nude mouse sacrifice.
- Tumor growth inhibition rate (%) (1-the average tumor weight of the treatment group/ the average tumor weight of the model group) ⁇ 100%.
- each drug-administered group has a certain degree of inhibition on the tumor growth inhibition rate, tumor volume, relative tumor volume and relative tumor proliferation rate (see Table 12, and Table 13).
- the tumor growth inhibition rates of isovaleryl spiramycin I groups with low, medium and high doses are 33.87%, 51.33% and 71.01%, respectively.
- the tumor growth inhibition rates of isovaleryl spiramycin II groups with low, medium and high doses are 23.49%, 40.16% and 50.44%, respectively.
- the tumor growth inhibition rates of isovaleryl spiramycin III groups with low, medium and high doses are 25.44%, 40.16% and 60.37%, respectively.
- the tumor volume and relative tumor volume of isovaleryl spiramycin I, II and III groups with low, medium and high doses are significantly lower than those of the model group (P ⁇ 0.05).
- the relative tumor proliferation rates of isovaleryl spiramycin I groups with low, medium and high doses are 70.43%, 49.14% and 30.72%, respectively.
- the relative tumor proliferation rates of isovaleryl spiramycin II groups with low, medium and high doses are 83.04%, 60.08% and 44.48%, respectively.
- the relative tumor proliferation rates of isovaleryl spiramycin III groups with low, medium and high doses are 75.75%, 55.02% and 34.57%, respectively.
- MCF-7 cells in a logarithmic growth phase were taken and subjected to trypan blue exclusion experiment showing that the cell viability was more than 95%, then the cells were subjected to trypsinization, centrifugation, and supernatant removal. Then cell concentration was adjusted to 1 ⁇ 10 7 /ml with matrigel, then each nude mouse was inoculated subcutaneously with 0.2ml of cells at its right armpit and recorded as the first day of inoculation.
- mice When the tumor grows to be greater than or equal to 100 mm 3 , the mice were randomly divided into 11 groups with 6 mice in each group: a model group, a cyclophosphamide group, isovaleryl spiramycin I groups with doses of 25, 50 and 100 mg/kg, isovaleryl spiramycin II groups with doses of 25, 50 and 100 mg/kg, and isovaleryl spiramycin III groups with doses of 25, 50 and 100 mg/kg. Each group was continuously administered intragastrically for 30 days with a dose of 20 ml/kg. The mice were sacrificed the next day after drug withdrawal and the indicators were tested. The long diameter and short diameter of the tumor, and the body weight of each mouse were recorded every 3 days from drug administration to nude mouse sacrifice.
- Tumor growth inhibition rate (%) (1-the average tumor weight of the treatment group/ the average tumor weight of the model group) ⁇ 100%.
- each drug-administered group has a certain degree of inhibition on the tumor growth inhibition rate, tumor volume, relative tumor volume and relative tumor proliferation rate (see Table 14, and Table 15).
- the tumor growth inhibition rates of isovaleryl spiramycin I groups with low, medium and high doses are 31.10%, 51.72% and 70.12%, respectively.
- the tumor growth inhibition rates of isovaleryl spiramycin II groups with low, medium and high doses are 20.55%, 41.72% and 56.81%, respectively.
- the tumor growth inhibition rates of isovaleryl spiramycin III groups with low, medium and high doses are 26.75%, 39.08% and 61.78%, respectively.
- the tumor volume and relative tumor volume of isovaleryl spiramycin I, II and III groups with low, medium and high doses are significantly lower than those of the model group (P ⁇ 0.05).
- the relative tumor proliferation rates of isovaleryl spiramycin I groups with low, medium and high doses are 71.92%, 49.05% and 30.80%, respectively.
- the relative tumor proliferation rates of isovaleryl spiramycin II groups with low, medium and high doses are 79.23%, 60.58% and 44.44%, respectively.
- the relative tumor proliferation rates of isovaleryl spiramycin III groups with low, medium and high doses are 75.03%, 54.92% and 34.91%, respectively.
- MDA-MB-231 cells in a logarithmic growth phase were taken and subjected to a trypan blue exclusion experiment showing that the cell viability was more than95%, then the cells were subjected to trypsinization, centrifugation, and supernatant removal. Then cell concentration was adjusted to 1 ⁇ 10 7 /ml with matrigel, then each nude mouse was inoculated subcutaneously with 0.2ml of cells at its right armpit and recorded as the first day of inoculation.
- mice When the tumor grows to be greater than or equal to 100 mm 3 , the mice were randomly divided into 11 groups with 6 mice in each group: a model group, a cyclophosphamide group, isovaleryl spiramycin I groups with doses of 25, 50 and 100 mg/kg, isovaleryl spiramycin II groups with doses of 25, 50 and 100 mg/kg, and isovaleryl spiramycin III groups with doses of 25, 50 and 100 mg/kg. Each group was continuously administered intragastrically for 30 days with a dose of 20 ml/kg. The mice were sacrificed the next day after drug withdrawal and the indicators were tested. The long diameter and short diameter of the tumor, and the body weight of each mouse were recorded every 3 days from drug administration to nude mouse sacrifice.
- Tumor growth inhibition rate (%) (1-the average tumor weight of the treatment group/ the average tumor weight of the model group) ⁇ 100%.
- each drug-administered group has a certain degree of inhibition on the tumor growth inhibition rate, tumor volume, relative tumor volume and relative tumor proliferation rate (see Table 16, and Table 17).
- the tumor growth inhibition rates of isovaleryl spiramycin I groups with low, medium and high doses are 22.84%, 55.17% and 69.11%, respectively.
- the tumor growth inhibition rates of isovaleryl spiramycin II groups with low, medium and high doses are 18.17%, 29.66% and 58.91%, respectively.
- the tumor growth inhibition rates of isovaleryl spiramycin III groups with low, medium and high doses are 24.35%, 21.01% and 62.93%, respectively.
- the tumor volume and relative tumor volume of isovaleryl spiramycin I, II and III groups with low, medium and high doses are significantly lower than those of the model group (P ⁇ 0.05).
- the relative tumor proliferation rates of isovaleryl spiramycin I groups with low, medium and high doses are 69.71%, 44.18% and 27.74%, respectively.
- the relative tumor proliferation rates of isovaleryl spiramycin II groups with low, medium and high doses are 80.22%, 58.78% and 30.89%, respectively.
- the relative tumor proliferation rates of isovaleryl spiramycin III groups with low, medium and high doses were 68.36%, 50.12% and 35.27%, respectively.
- PANC-1 cells in a logarithmic growth phase were taken and subjected to a trypan blue exclusion experiment showing that the cell viability was more than95%, then the cells were subjected to trypsinization, centrifugation, and supernatant removal. Then cell concentration was adjusted to 1 ⁇ 10 7 /ml with matrigel, then each nude mouse was inoculated subcutaneously with 0.2ml of cells at its right armpit and recorded as the first day of inoculation.
- mice When the tumor grows to be greater than or equal to 100 mm 3 , the mice were randomly divided into 11 groups with 6 mice in each group: a model group, a cyclophosphamide group, isovaleryl spiramycin I groups with doses of 25, 50 and 100 mg/kg, isovaleryl spiramycin II groups with doses of 25, 50 and 100 mg/kg, and isovaleryl spiramycin III groups with doses of 25, 50 and 100 mg/kg. Each group was continuously administered intragastrically for 30 days with a dose of 20 ml/kg. The mice were sacrificed the next day after drug withdrawal and the indicators were tested. The long diameter and short diameter of the tumor, and the body weight of each mouse were recorded every 3 days from drug administration to nude mouse sacrifice.
- Tumor growth inhibition rate (%) (1-the average tumor weight of the treatment group/ the average tumor weight of the model group) ⁇ 100%.
- each drug-administered group has a certain degree of inhibition on the tumor growth inhibition rate, tumor volume, relative tumor volume and relative tumor proliferation rate (see Table 18, and Table 19).
- the tumor growth inhibition rates of isovaleryl spiramycin I groups with low, medium and high doses are 31.10%, 51.72% and 70.12%, respectively.
- the tumor growth inhibition rates of isovaleryl spiramycin II groups with low, medium and high doses are 20.55%, 41.72% and 56.81%, respectively.
- the tumor growth inhibition rates of isovaleryl spiramycin III groups with low, medium and high doses are 26.75%, 39.08% and 61.78%, respectively.
- the tumor volume and relative tumor volume of isovaleryl spiramycin I, II and III groups with low, medium and high doses are significantly lower than those of the model group (P ⁇ 0.05).
- the relative tumor proliferation rates of isovaleryl spiramycin I groups with low, medium and high doses are 71.92%, 49.05% and 30.80%, respectively.
- the relative tumor proliferation rates of isovaleryl spiramycin II groups with low, medium and high doses are 79.23%, 60.58% and 44.44%, respectively.
- the relative tumor proliferation rates of isovaleryl spiramycin III groups with low, medium and high doses are 75.03%, 54.92% and 34.91%, respectively.
- HepG-2 cells in a logarithmic growth phase were taken and subjected to a trypan blue exclusion experiment showing that the cell viability was more than 95%, then the cells were subjected to trypsinization, centrifugation, and supernatant removal. Then cell concentration was adjusted to 1 ⁇ 10 7 /ml with matrigel, then each nude mouse was inoculated subcutaneously with 0.2ml of cells at its right armpit and recorded as the first day of inoculation.
- mice When the tumor grows to be greater than or equal to 100 mm 3 , the mice were randomly divided into 11 groups with 6 mice in each group: a model group, a cyclophosphamide group, isovaleryl spiramycin I groups with doses of 25, 50 and 100 mg/kg, isovaleryl spiramycin II groups with doses of 25, 50 and 100 mg/kg, and isovaleryl spiramycin III groups with doses of 25, 50 and 100 mg/kg. Each group was continuously administered intragastrically for 30 days with a dose of 20 ml/kg. The mice were sacrificed the next day after drug withdrawal and the indicators were tested. The long diameter and short diameter of the tumor, and the body weight of each mouse were recorded every 3 days from drug administration to nude mouse sacrifice.
- Tumor growth inhibition rate (%) (1-the average tumor weight of the treatment group/ the average tumor weight of the model group) ⁇ 100%.
- each drug-administered group has a certain degree of inhibition on the tumor growth inhibition rate, tumor volume, relative tumor volume and relative tumor proliferation rate (see Table 20, and Table 21).
- the tumor growth inhibition rates of isovaleryl spiramycin I groups with low, medium and high doses are 24.43%, 57.93% and 68.22%, respectively.
- the tumor growth inhibition rates of isovaleryl spiramycin II groups with low, medium and high doses are 21.07%, 31.43% and 61.56%, respectively.
- the tumor growth inhibition rates of isovaleryl spiramycin III groups with low, medium and high doses of are 38.92%, 60.54% and 63.28%, respectively.
- the tumor volume and relative tumor volume of isovaleryl spiramycin I, II and III groups with low, medium and high doses are significantly lower than those of the model group (P ⁇ 0.05).
- the relative tumor proliferation rates of isovaleryl spiramycin I groups with low, medium and high doses are 65.03%, 42.12% and 27.49%, respectively.
- the relative tumor proliferation rates of isovaleryl spiramycin II groups with low, medium and high doses are 81.03%, 57.02% and 39.31%, respectively.
- the relative tumor proliferation rates of isovaleryl spiramycin III groups with low, medium and high doses are 64.69%, 43.18% and 32.71%, respectively.
- A549 cells in a logarithmic growth phase were taken and subjected to a trypan blue exclusion experiment showing that the cell viability was more than 95%, then the cells were subjected to trypsinization, centrifugation, and supernatant removal. Then cell concentration was adjusted to 1 ⁇ 10 7 /ml with matrigel, then each nude mouse was inoculated subcutaneously with 0.2ml of cells at its right armpit and recorded as the first day of inoculation.
- mice When the tumor grows to be greater than or equal to 100 mm 3 , the mice were randomly divided into 11 groups with 6 mice in each group: a model group, a cyclophosphamide group, isovaleryl spiramycin I groups with doses of 25, 50 and 100 mg/kg, isovaleryl spiramycin II groups with doses of 25, 50 and 100 mg/kg, and isovaleryl spiramycin III groups with doses of 25, 50 and 100 mg/kg. Each group was continuously administered intragastrically for 30 days with a dose of 20 ml/kg. The mice were sacrificed the next day after drug withdrawal and the indicators were tested. The long diameter and short diameter of the tumor, and the body weight of each mouse were recorded every 3 days from drug administration to nude mouse sacrifice.
- Tumor growth inhibition rate (%) (1-the average tumor weight of the treatment group/ the average tumor weight of the model group) ⁇ 100%.
- each drug-administered group has a certain degree of inhibition on the tumor growth inhibition rate, tumor volume, relative tumor volume and relative tumor proliferation rate (see Table 22, and Table 23).
- the tumor growth inhibition rates of isovaleryl spiramycin I groups with low, medium and high doses are 24.00%, 58.10% and 69.52%, respectively.
- the tumor growth inhibition rates of isovaleryl spiramycin II groups with low, medium and high doses are 20.73%, 31.87% and 60.19%, respectively.
- the tumor growth inhibition rates of isovaleryl spiramycin III groups with low, medium and high doses are 37.99%, 55.95% and 66.53%, respectively.
- the tumor volume and relative tumor volume of isovaleryl spiramycin I, II and III groups with low, medium and high doses are significantly lower than those of the model group (P ⁇ 0.05).
- the relative tumor proliferation rates of isovaleryl spiramycin I groups with low, medium and high doses are 67.18%, 41.93% and 28.35%, respectively.
- the relative tumor proliferation rates of isovaleryl spiramycin II groups with low, medium and high doses are 83.41%, 58.75% and 39.42%, respectively.
- the relative tumor proliferation rates of isovaleryl spiramycin III groups with low, medium and high doses are 65.93%, 47.25% and 33.04%, respectively.
- mice When the tumor grows to be greater than or equal to 100 mm 3 , the mice were randomly divided into 11 groups with 6 mice in each group: a model group, a cyclophosphamide group, isovaleryl spiramycin I groups with doses of 25, 50 and 100 mg/kg, isovaleryl spiramycin II groups with doses of 25, 50 and 100 mg/kg, and isovaleryl spiramycin III groups with doses of 25, 50 and 100 mg/kg. Each group was continuously administered intragastrically for 30 days with a dose of 20 ml/kg. The mice were sacrificed the next day after drug withdrawal and the indicators were tested. The long diameter and short diameter of the tumor, and the body weight of each mouse were recorded every 3 days from drug administration to nude mouse sacrifice.
- Tumor growth inhibition rate (%) (1-the average tumor weight of the treatment group/ the average tumor weight of the model group) ⁇ 100%.
- each drug-administered group has a certain degree of inhibition on the tumor growth inhibition rate, tumor volume, relative tumor volume and relative tumor proliferation rate (see Table 24, and Table 25).
- the tumor growth inhibition rates of isovaleryl spiramycin I groups with low, medium and high doses are 30.94%, 44.53% and 69.21%, respectively.
- the tumor growth inhibition rates of isovaleryl spiramycin II groups with low, medium and high doses are 10.91%, 15.81% and 40.26%, respectively.
- the tumor growth inhibition rates of isovaleryl spiramycin III groups with low, medium and high doses are 15.45%, 32.74% and 59.56%, respectively.
- the tumor volume and relative tumor volume of isovaleryl spiramycin I, II and III groups with low, medium and high doses are significantly lower than those of the model group (P ⁇ 0.05).
- the relative tumor proliferation rates of isovaleryl spiramycin I groups with low, medium and high doses are 76.40%, 44.54% and 25.80%, respectively.
- the relative tumor proliferation rates of isovaleryl spiramycin II groups with low, medium and high doses are 76.14%, 51.88% and 43.26%, respectively.
- the relative tumor proliferation rates of isovaleryl spiramycin III groups with low, medium and high doses are 68.16%, 54.34% and 41.10%, respectively.
- A172 cells in a logarithmic growth phase were taken and subjected to a trypan blue exclusion experiment showing that the cell viability was more than 95%, then the cells were subjected to trypsinization, centrifugation, and supernatant removal. Then cell concentration was adjusted to 1 ⁇ 10 7 /ml with matrigel, then each nude mouse was inoculated subcutaneously with 0.2ml of cells at its right armpit and recorded as the first day of inoculation.
- mice When the tumor grows to be greater than or equal to 100 mm 3 , the mice were randomly divided into 11 groups with 6 mice in each group: a model group, a temozolomide group, isovaleryl spiramycin I groups with doses of 25, 50 and 100 mg/kg, isovaleryl spiramycin II groups with doses of 25, 50 and 100 mg/kg, and isovaleryl spiramycin III groups with doses of 25, 50 and 100 mg/kg. Each group was continuously administered intragastrically for 30 days with a dose of 20 ml/kg. The mice were sacrificed the next day after drug withdrawal and the indicators were tested. The long diameter and short diameter of the tumor, and the body weight of each mouse were recorded every 3 days from drug administration to nude mouse sacrifice.
- Tumor growth inhibition rate (%) (1-the average tumor weight of the treatment group/ the average tumor weight of the model group) ⁇ 100%.
- each drug-administered group has a certain degree of inhibition on the tumor growth inhibition rate, tumor volume, relative tumor volume and relative tumor proliferation rate (see Table 26, and Table 27).
- the tumor growth inhibition rates of isovaleryl spiramycin I groups with low, medium and high doses are 30.75%, 44.26% and 68.79%, respectively.
- the tumor growth inhibition rates of isovaleryl spiramycin II groups with low, medium and high doses are 10.85%, 15.71% and 40.01%, respectively.
- the tumor growth inhibition rates of isovaleryl spiramycin III groups with low, medium and high doses are 15.35%, 32.54% and 59.19%, respectively.
- the tumor volume and relative tumor volume of isovaleryl spiramycin I, II and III groups with low, medium and high doses are significantly lower than those of the model group (P ⁇ 0.05).
- the relative tumor proliferation rates of isovaleryl spiramycin I groups with low, medium and high doses are 74.49%, 43.43% and 25.16%, respectively.
- the relative tumor proliferation rates of isovaleryl spiramycin II groups with low, medium and high doses are 74.24%, 50.59% and 42.18%, respectively.
- the relative tumor proliferation rates of isovaleryl spiramycin III groups with low, medium and high doses are 66.45%, 52.89% and 40.08%, respectively.
- mice When the tumor grows to be greater than or equal to 100 mm 3 , the mice were randomly divided into 11 groups with 6 mice in each group: a model group, a cyclophosphamide group, isovaleryl spiramycin I groups with doses of 25, 50 and 100 mg/kg, isovaleryl spiramycin II groups with doses of 25, 50 and 100 mg/kg, and isovaleryl spiramycin III groups with doses of 25, 50 and 100 mg/kg. Each group was continuously administered intragastrically for 30 days with a dose of 20 ml/kg. The mice were sacrificed the next day after drug withdrawal and the indicators were tested. The long diameter and short diameter of the tumor, and the body weight of each mouse were recorded every 3 days from drug administration to nude mouse sacrifice.
- Tumor growth inhibition rate (%) (1-the average tumor weight of the treatment group/ the average tumor weight of the model group) ⁇ 100%.
- each drug-administered group has a certain degree of inhibition on the tumor growth inhibition rate, tumor volume, relative tumor volume and relative tumor proliferation rate (see Table 28, and Table 29).
- the tumor growth inhibition rates of isovaleryl spiramycin I groups with low, medium and high doses are 41.73%, 50.73% and 65.03%, respectively.
- the tumor growth inhibition rates of isovaleryl spiramycin II groups with low, medium and high doses are 25.61%, 35.44% and 43.63%, respectively.
- the tumor growth inhibition rates of isovaleryl spiramycin III groups with low, medium and high doses are 41.19%, 53.03% and 61.77%, respectively.
- the tumor volume and relative tumor volume of isovaleryl spiramycin I, II and III groups with low, medium and high doses are significantly lower than those of the model group (P ⁇ 0.05).
- the relative tumor proliferation rates of isovaleryl spiramycin I groups with low, medium and high doses are 68.65%, 39.74% and 35.25%, respectively.
- the relative tumor proliferation rates of isovaleryl spiramycin II groups with low, medium and high doses are 74.19%, 52.10% and 46.09%, respectively.
- the relative tumor proliferation rates of isovaleryl spiramycin III groups with low, medium and high doses are 63.36%, 49.30% and 38.66%, respectively.
- HeLa cells in a logarithmic growth phase were taken and subjected to a trypan blue exclusion experiment showing that the cell viability was more than 95%, then the cells were subjected to trypsinization, centrifugation, and supernatant removal. Then cell concentration was adjusted to 1 ⁇ 10 7 /ml with matrigel, then each nude mouse was inoculated subcutaneously with 0.2ml of cells at its right armpit and recorded as the first day of inoculation.
- mice When the tumor grows to be greater than or equal to 100 mm 3 , the mice were randomly divided into 11 groups with 6 mice in each group: a model group, a cyclophosphamide group, isovaleryl spiramycin I groups with doses of 25, 50 and 100 mg/kg, isovaleryl spiramycin II groups with doses of 25, 50 and 100 mg/kg, and isovaleryl spiramycin III groups with doses of 25, 50 and 100 mg/kg. Each group was continuously administered intragastrically for 30 days with a dose of 20 ml/kg. The mice were sacrificed the next day after drug withdrawal and the indicators were tested. The long diameter and short diameter of the tumor, and the body weight of each mouse were recorded every 3 days from drug administration to nude mouse sacrifice.
- Tumor growth inhibition rate (%) (1-the average tumor weight of the treatment group/ the average tumor weight of the model group) ⁇ 100%.
- each drug-administered group has a certain degree of inhibition on the tumor growth inhibition rate, tumor volume, relative tumor volume and relative tumor proliferation rate (see Table 30, and Table 31).
- the tumor growth inhibition rates of isovaleryl spiramycin I groups with low, medium and high doses are 46.69%, 51.57% and 65.55%, respectively.
- the tumor growth inhibition rates of isovaleryl spiramycin II groups with low, medium and high doses are 30.67%, 42.90% and 43.30%, respectively.
- the tumor growth inhibition rates of isovaleryl spiramycin III groups with low, medium and high doses are 39.33%, 52.41% and 61.68%, respectively.
- the tumor volume and relative tumor volume of isovaleryl spiramycin I, II and III groups with low, medium and high doses are significantly lower than those of the model group (P ⁇ 0.05).
- the relative tumor proliferation rates of isovaleryl spiramycin I groups with low, medium and high doses are 69.18%, 39.57% and 30.91%, respectively.
- the relative tumor proliferation rates of isovaleryl spiramycin II groups with low, medium and high doses are 30.67%, 42.90% and 43.30%, respectively.
- the relative tumor proliferation rates of isovaleryl spiramycin III groups with low, medium and high doses are 39.33%, 52.41% and 61.68%, respectively.
- mice When the tumor grows to be greater than or equal to 100 mm 3 , the mice were randomly divided into 11 groups with 6 mice in each group: a model group, a cyclophosphamide group, isovaleryl spiramycin I groups with doses of 25, 50 and 100 mg/kg, isovaleryl spiramycin II groups with doses of 25, 50 and 100 mg/kg, and isovaleryl spiramycin III groups with doses of 25, 50 and 100 mg/kg. Each group was continuously administered intragastrically for 30 days with a dose of 20 ml/kg. The mice were sacrificed the next day after drug withdrawal and the indicators were tested. The long diameter and short diameter of the tumor, and the body weight of each mouse were recorded every 3 days from drug administration to nude mouse sacrifice.
- Tumor growth inhibition rate (%) (1-the average tumor weight of the treatment group/ the average tumor weight of the model group) ⁇ 100%.
- each drug-administered group has a certain degree of inhibition on the tumor growth inhibition rate, tumor volume, relative tumor volume and relative tumor proliferation rate (see Table 32, and Table 33).
- the tumor growth inhibition rates of isovaleryl spiramycin I groups with low, medium and high doses are 34.70%, 39.22% and 64.36%, respectively.
- the tumor growth inhibition rates of isovaleryl spiramycin II groups with low, medium and high doses are 19.69%, 41.09% and 60.00%, respectively.
- the tumor growth inhibition rates of isovaleryl spiramycin III groups with low, medium and high doses are 35.80%, 52.14% and 62.49%, respectively.
- the tumor volume and relative tumor volume of isovaleryl spiramycin I, II and III groups with low, medium and high doses are significantly lower than those of the model group (P ⁇ 0.05).
- the relative tumor proliferation rates of isovaleryl spiramycin I groups with low, medium and high doses are 37.88%, 37.19% and 36.89%, respectively.
- the relative tumor proliferation rates of isovaleryl spiramycin II groups with low, medium and high doses are 76.92%, 53.61% and 35.74%, respectively.
- the relative tumor proliferation rates of isovaleryl spiramycin III groups with low, medium and high doses are 73.13%, 51.33% and 34.20%, respectively.
- mice When the tumor grows to be greater than or equal to 100 mm 3 , the mice were randomly divided into 11 groups with 6 mice in each group: a model group, a cyclophosphamide group, isovaleryl spiramycin I groups with doses of 25, 50 and 100 mg/kg, isovaleryl spiramycin II groups with doses of 25, 50 and 100 mg/kg, and isovaleryl spiramycin III groups with doses of 25, 50 and 100 mg/kg. Each group was continuously administered intragastrically for 30 days with a dose of 20 ml/kg. The mice were sacrificed the next day after drug withdrawal and the indicators were tested. The long diameter and short diameter of the tumor, and the weight of each mouse were recorded every 3 days from drug administration to nude mouse sacrifice.
- Tumor growth inhibition rate (%) (1-the average tumor weight of the treatment group/ the average tumor weight of the model group) ⁇ 100%.
- each drug-administered group has a certain degree of inhibition on the tumor growth inhibition rate, tumor volume, relative tumor volume and relative tumor proliferation rate (see Table 34, and Table 35).
- the tumor growth inhibition rates of isovaleryl spiramycin I groups with low, medium and high doses are 33.68%, 47.33% and 68.82%, respectively.
- the tumor growth inhibition rates of isovaleryl spiramycin II groups with low, medium and high doses are 38.29%, 47.61% and 61.79%, respectively.
- the tumor growth inhibition rates of isovaleryl spiramycin III groups with low, medium and high doses are 40.87%, 60.50% and 64.46%, respectively.
- the tumor volume and relative tumor volume of isovaleryl spiramycin I, II and III groups with low, medium and high doses are significantly lower than those of the model group (P ⁇ 0.05).
- the relative tumor proliferation rates of isovaleryl spiramycin I groups with low, medium and high doses are 75.78%, 57.12% and 36.88%, respectively.
- the relative tumor proliferation rates of isovaleryl spiramycin II groups with low, medium and high doses are 68.22%, 42.64% and 34.76%, respectively.
- the relative tumor proliferation rates of isovaleryl spiramycin III groups with low, medium and high doses are 61.59%, 51.59% and 35.55%, respectively.
- HT-29 cells in a logarithmic growth phase were taken and subjected to a trypan blue exclusion experiment showing that the cell viability was more than 95%, then the cells were subjected to trypsinization, centrifugation, and supernatant removal. Then cell concentration was adjusted to 1 ⁇ 10 7 /ml with matrigel, then each nude mouse was inoculated subcutaneously with 0.2ml of cells at its right armpit and recorded as the first day of inoculation.
- mice When the tumor grows to be greater than or equal to 100 mm 3 , the mice were randomly divided into 11 groups with 6 mice in each group: isovaleryl spiramycin I groups with doses of 25, 50 and 100 mg/kg, isovaleryl spiramycin II groups with doses of 25, 50 and 100 mg/kg, and isovaleryl spiramycin III groups with doses of 25, 50 and 100 mg/kg. Each group was continuously administered intragastrically for 30 days with a dose of 20 ml/kg. The mice were sacrificed the next day after drug withdrawal and the indicators were tested. The long diameter and short diameter of the tumor, and the body weight of each mouse were recorded every 3 days from drug administration to nude mouse sacrifice.
- Tumor growth inhibition rate (%) (1-the average tumor weight of the treatment group/ the average tumor weight of the model group) ⁇ 100%.
- each drug-administered group has a certain degree of inhibition on the tumor growth inhibition rate, tumor volume, relative tumor volume and relative tumor proliferation rate (see Table 36, and Table 37).
- the tumor growth inhibition rates of isovaleryl spiramycin I groups with low, medium and high doses are 16.10%, 49.72% and 70.14%, respectively.
- the tumor growth inhibition rates of isovaleryl spiramycin II groups with low, medium and high doses are 16.24%, 32.41% and 55.74%, respectively.
- the tumor growth inhibition rates of isovaleryl spiramycin III groups with low, medium and high doses are 19.22%, 41.35% and 63.19%, respectively.
- the tumor volume and relative tumor volume of isovaleryl spiramycin I, II and III groups with low, medium and high doses are significantly lower than those of the model group (P ⁇ 0.05).
- the relative tumor proliferation rates of isovaleryl spiramycin I groups with low, medium and high doses are 81.60%, 49.22% and 29.11%, respectively.
- the relative tumor proliferation rates of isovaleryl spiramycin II groups with low, medium and high doses are 84.18%, 79.34% and 44.05%, respectively.
- the relative tumor proliferation rates of isovaleryl spiramycin III groups with low, medium and high doses are 85.54%, 53.48% and 35.63%, respectively.
- HL-60 cells in a logarithmic growth phase were taken and subjected to a trypan blue exclusion experiment showing that the cell viability was more than 95%, then the cells were subjected to trypsinization, centrifugation, and supernatant removal. Then cell concentration was adjusted to 1 ⁇ 10 7 /ml with matrigel, then each nude mouse was inoculated subcutaneously with 0.2ml of cells at its right armpit and recorded as the first day of inoculation.
- mice When the tumor grows to be greater than or equal to 100 mm 3 , the mice were randomly divided into 11 groups with 6 mice in each group: isovaleryl spiramycin I groups with doses of 25, 50 and 100 mg/kg, isovaleryl spiramycin II groups with doses of 25, 50 and 100 mg/kg, and isovaleryl spiramycin III groups with doses of 25, 50 and 100 mg/kg. Each group was continuously administered intragastrically for 30 days with a dose of 20 ml/kg. The mice were sacrificed the next day after drug withdrawal and the indicators were tested. The long diameter and short diameter of the tumor, and the weight of each mouse were recorded every 3 days from drug administration to nude mouse sacrifice.
- Tumor growth inhibition rate (%) (1-the average tumor weight of the treatment group/ the average tumor weight of the model group) ⁇ 100%.
- each drug-administered group has a certain degree of inhibition on the tumor growth inhibition rate, tumor volume, relative tumor volume and relative tumor proliferation rate (see Table 38, and Table 39).
- the tumor growth inhibition rates of isovaleryl spiramycin I groups with low, medium and high doses are 11.57%, 34.78% and 64.19%, respectively.
- the tumor growth inhibition rates of isovaleryl spiramycin II groups with low, medium and high doses are 15.92%, 29.48% and 51.81%, respectively.
- the tumor growth inhibition rates of isovaleryl spiramycin III groups with low, medium and high doses are 17.10%, 29.92% and 55.05%, respectively.
- the tumor volume and relative tumor volume of isovaleryl spiramycin I, II and III groups with low, medium and high doses are significantly lower than those of the model group (P ⁇ 0.05).
- the relative tumor proliferation rates of isovaleryl spiramycin I groups with low, medium and high doses are 84.96%, 59.54% and 32.70%, respectively.
- the relative tumor proliferation rates of isovaleryl spiramycin II groups with low, medium and high doses are 75.39%, 65.18% and 41.36%, respectively.
- the relative tumor proliferation rates of isovaleryl spiramycin III groups with low, medium and high doses are 76.09%, 61.90% and 39.87%, respectively.
- TPC-1 cells in a logarithmic growth phase were taken and subjected to a trypan blue exclusion experiment showing that the cell viability was more than 95%, then the cells were subjected to trypsinization, centrifugation, and supernatant removal. Then cell concentration was adjusted to 1 ⁇ 10 7 /ml with matrigel, then each nude mouse was inoculated subcutaneously with 0.2ml of cells at its right armpit and recorded as the first day of inoculation.
- mice When the tumor grows to be greater than or equal to 100 mm 3 , the mice were randomly divided into 11 groups with 6 mice in each group: isovaleryl spiramycin I groups with doses of 25, 50 and 100 mg/kg, isovaleryl spiramycin II groups with doses of 25, 50 and 100 mg/kg, and isovaleryl spiramycin III groups with doses of 25, 50 and 100 mg/kg. Each group was continuously administered intragastrically for 30 days with a dose of 20 ml/kg. The mice were sacrificed the next day after drug withdrawal and the indicators were tested. The long diameter and short diameter of the tumor, and the body weight of each mouse were recorded every 3 days from drug administration to nude mouse sacrifice.
- Tumor growth inhibition rate (%) (1-the average tumor weight of the treatment group/ the average tumor weight of the model group) ⁇ 100%.
- each drug-administered group has a certain degree of inhibition on the tumor growth inhibition rate, tumor volume, relative tumor volume and relative tumor proliferation rate (see Table 40, and Table 41).
- the tumor growth inhibition rates of isovaleryl spiramycin I groups with low, medium and high doses are 23.88%, 57.28% and 67.49%, respectively.
- the tumor growth inhibition rates of isovaleryl spiramycin II groups with low, medium and high doses are 20.91%, 31.61% and 62.04%, respectively.
- the tumor growth inhibition rates of isovaleryl spiramycin III groups with low, medium and high doses are 39.06%, 60.25% and 62.94%, respectively.
- the tumor volume and relative tumor volume of isovaleryl spiramycin I, II and III groups with low, medium and high doses are significantly lower than those of the model group (P ⁇ 0.05).
- the relative tumor proliferation rates of isovaleryl spiramycin I groups with low, medium and high doses are 65.45%, 43.43% and 28.11%, respectively.
- the relative tumor proliferation rates of isovaleryl spiramycin II groups with low, medium and high doses are 86.15%, 59.08% and 38.61%, respectively.
- the relative tumor proliferation rates of isovaleryl spiramycin III groups with low, medium and high doses are 61.93%, 45.01% and 34.75%, respectively.
- T-24 cells in a logarithmic growth phase were taken and subjected to a trypan blue exclusion experiment showing that the cell viability was more than 95%, then the cells were subjected to trypsinization, centrifugation, and supernatant removal. Then cell concentration was adjusted to 1 ⁇ 10 7 /ml with matrigel, then each nude mouse was inoculated subcutaneously with 0.2ml of cells at its right armpit and recorded as the first day of inoculation.
- mice When the tumor grows to be greater than or equal to 100 mm 3 , the mice were randomly divided into 11 groups with 6 mice in each group: isovaleryl spiramycin I groups with doses of 25, 50 and 100 mg/kg, isovaleryl spiramycin II groups with doses of 25, 50 and 100 mg/kg, and isovaleryl spiramycin III groups with doses of 25, 50 and 100 mg/kg. Each group was continuously administered intragastrically for 30 days with a dose of 20 ml/kg. The mice were sacrificed the next day after drug withdrawal and the indicators were tested. The long diameter and short diameter of the tumor, and the body weight of each mouse were recorded every 3 days from drug administration to nude mouse sacrifice.
- Tumor growth inhibition rate (%) (1-the average tumor weight of the treatment group/ the average tumor weight of the model group) ⁇ 100%.
- each drug-administered group has a certain degree of inhibition on the tumor growth inhibition rate, tumor volume, relative tumor volume and relative tumor proliferation rate (see Table 42, and Table 43).
- the tumor growth inhibition rates of isovaleryl spiramycin I groups with low, medium and high doses are 20.55%, 49.20% and 65.84%, respectively.
- the tumor growth inhibition rates of isovaleryl spiramycin II groups with low, medium and high doses are 15.57%, 41.99% and 59.25%, respectively.
- the tumor growth inhibition rates of isovaleryl spiramycin III groups with low, medium and high doses are 21.00%, 44.84% and 61.30%, respectively.
- the tumor volume and relative tumor volume of isovaleryl spiramycin I, II and III groups with low, medium and high doses are significantly lower than those of the model group (P ⁇ 0.05).
- the relative tumor proliferation rates of isovaleryl spiramycin I groups with low, medium and high doses are 77.78%, 58.92% and 33.95%, respectively.
- the relative tumor proliferation rates of isovaleryl spiramycin II groups with low, medium and high doses are 81.39%, 64.89% and 46.70%, respectively.
- the relative tumor proliferation rates of isovaleryl spiramycin III groups with low, medium and high doses are 80.34%, 62.35% and 39.39%, respectively.
- the H 22 cell strains cryopreserved in liquid nitrogen were resuscitated in Kunming mice. After 3 generations, the ascites of Kunming mice were taken and placed in a 50 ml centrifuge tube in which 10 ml of 0.9% normal saline was added, and then centrifuging was performed at 1000rpm for 5 min at room temperature, and the obtained supernatant was removed. Then 10 ml of 0.9% normal saline was added to the tube to blow and mix well, and then the mixture was diluted to 5 ⁇ 10 6 live cells /ml with normal saline after counting. The tube was stored in ice water, and 75% ethanol was used to disinfect the skin under the right armpits of the mice. Each Kunming mouse was soon inoculated subcutaneously with 0.2ml of the cells at the armpit of the right forelimb.
- Lewis lung cancer cells were cultured in a RPMI 1640 culture medium containing 10% fetal bovine serum at 37°C in a 5% CO 2 incubator. The cells in the logarithmic growth phase were subjected to trypsinization with 0.25% trypsin, then the cells were collected to be centrifugated to remove the obtained supernatant, then were washed twice with sterile normal saline. And then the cells were suspended in the normal saline to be subjected to a trypan blue staining assay which shows that the cell viability was greater than 95%, and then cell counting was performed. The Lewis cells were adjusted to 1 ⁇ 10 7 /mL in concentration and stored in ice water. 75% ethanol was used to disinfect the skin under the right armpits of the mice, and each C57BL/6 mouse was soon inoculated subcutaneously with 0.2 ml of the cells at its right armpit.
- mice inoculated with the tumor were randomly divided into groups with 10 mice in each group on the next day of inoculation.
- CTX positive drug cyclophosphamide control group
- isovaleryl spiramycin I groups with doses of 13, 26 and 52mg/kg
- isovaleryl spiramycin II groups with doses of 13, 26 and 52mg/kg
- isovaleryl spiramycin III groups with doses of 13, 26 and 52mg/kg.
- Each group was continuously administered intragastrically for 7 days with a dose of 20 ml/kg.
- mice inoculated with the tumor were randomly divided into groups with 10 mice in each group the next day of inoculation.
- CTX positive drug cyclophosphamide control group
- Tumor inhibition rate 1 ⁇ T / C ⁇ 100 %
- T average tumor weight of the drug-administered group
- C average tumor weight of the blank control group
- the tumor inhibition rate of the positive drug cyclophosphamide control group to Kunming mouse H 22 liver cancer is 73.03%.
- the positive drug cyclophosphamide group shows a slight decrease in weight compared with the normal control group.
- the weight of the mice in each of the isovaleryl spiramycin I, II and III groups increases compared with that before the administration, but there is no significant difference compared with the model control group. Table 44.
- the tumor inhibition rate of the positive drug cyclophosphamide control group to mouse Lewis lung cancer is 76.43%.
- Isovaleryl spiramycin I groups with doses of 13, 26 and 52mg/kg, isovaleryl spiramycin II groups with doses of 13, 26 and 52mg/kg, and isovaleryl spiramycin III groups with doses of 13, 26 and 52mg/kg significantly inhibit the growth of Lewis lung cancer in mice.
- the weight of the mice in each of the isovaleryl spiramycin I, II and III groups increases compared with that before the administration, but there is no significant difference compared with the model control group. Table 46.
- the spleen and thymus are weighed, and the spleen index and thymus index are calculated.
- the serum-free RPMI 1640 medium was placed in a dish, and then the dish was placed on ice.
- the spleen was aseptically taken and gently ground with a sterile glass slide to prepare a single cell suspension.
- the single cell suspension was filtered with a double-layer sterile gauze, washed twice with serum-free RPMI1640 medium, and centrifuged at 1,500 rpm for 5 min to remove the obtained supernatant.
- a single cell suspension was prepared by using a RPMI 1640 medium containing 10% fetal bovine serum.
- the spleen cell suspension was taken, and the cell density was adjusted to 1 ⁇ 10 7 /mL.
- Each mouse was set with: A. a control well: 100 ⁇ L of RPMI 1640 medium was added; B. a concanavalin A (ConA) stimulation well: 100 ⁇ L (10 mg/L) of concanavalin A (ConA) solution was added; and C. a bacterial endotoxin (LPS) stimulating well: 100 ⁇ L (20 mg/L) of bacterial endotoxin (LPS) solution was added.
- A. a control well 100 ⁇ L of RPMI 1640 medium was added
- B. a concanavalin A (ConA) stimulation well 100 ⁇ L (10 mg/L) of concanavalin A (ConA) solution was added
- C. a bacterial endotoxin (LPS) stimulating well 100 ⁇ L (20 mg/L) of bacterial endotoxin (LPS) solution was added.
- the above cells were added
- the spleen cell suspension was taken, and the cell density was adjusted to 1 ⁇ 10 7 /mL (effector cells).
- a suspension of K562 cells was prepared with a cell density of 1 ⁇ 10 5 /mL (target cells).
- target cells target cell well (quantity ratio 20:1) to which 20 ⁇ L of spleen cell suspension and 100 ⁇ L of K562 cell suspension were added;
- C a target cell control well to which 100 ⁇ L of K562 cell suspension and 100 ⁇ L of RPMI 1640 medium were added.
- the above cells were added to a 96-well plate. After the 96-well plate was transferred to a saturated humidity condition with a volume fraction of 5% CO 2 at 37°C for incubation for 22 h, 10 ⁇ L of MTT solution (5 g/L) was added to each well, and incubation was continued to be performed for 4 hours under the same conditions, , then the culture was terminated.
- NK cell activity (%) [TO-(S-E)]/TO ⁇ 100%, wherein TO is the Optical Density of the target cell control well, S is the Optical Density of the effector cell control well, and E is the Optical Density of the effector cell.
- the thymus index and spleen index of the positive drug cyclophosphamide control group are significantly lower than those of the control group (P ⁇ 0.01).
- the thymus indexes of the mice in the isovaleryl spiramycin I groups with doses of 13, 26 and 52mg/kg, isovaleryl spiramycin II groups with doses of 13, 26 and 52mg/kg, and isovaleryl spiramycin III groups with doses of 13, 26 and 52mg/kg have no significant change compared with that of the control group. Table 48.
- the spleen index of the positive drug cyclophosphamide control group is significantly lower than that of the control group (P ⁇ 0.01).
- the spleen index and thymus index of the mice in the isovaleryl spiramycin I groups with doses of 13, 26 and 52mg/kg, isovaleryl spiramycin II groups with doses of 13, 26 and 52mg/kg, and isovaleryl spiramycin III groups with doses of 13, 26 and 52mg/kg are not significantly different from those in the control group. Table 49.
- the NK cell activity of the positive drug cyclophosphamide control group is significantly lower than that of the control group (P ⁇ 0.05).
- the NK cell activities in isovaleryl spiramycin I groups with doses of 13, 26 and 52mg/kg, isovaleryl spiramycin II groups with doses of 13, 26 and 52mg/kg, and isovaleryl spiramycin III groups with doses of 13, 26 and 52mg/kg significantly increase compared with that of the control group (P ⁇ 0.01).
- Table 50 The NK cell activities in isovaleryl spiramycin I groups with doses of 13, 26 and 52mg/kg, isovaleryl spiramycin II groups with doses of 13, 26 and 52mg/kg, and isovaleryl spiramycin III groups with doses of 13, 26 and 52mg/kg significantly increase compared with that of the control group (P ⁇ 0.01). Table 50.
- the lymphocyte activity of the positive drug cyclophosphamide control group is significantly inhibited (P ⁇ 0.05).
- the lymphocyte activities of isovaleryl spiramycin I groups with doses of 13, 26 and 52mg/kg, isovaleryl spiramycin II groups with doses of 13, 26 and 52mg/kg, and isovaleryl spiramycin III groups with doses of 13, 26 and 52mg/kg significantly increase compared with that of the control group (P ⁇ 0.05, P ⁇ 0.01).
- Table 51 The lymphocyte activities of isovaleryl spiramycin I groups with doses of 13, 26 and 52mg/kg, isovaleryl spiramycin II groups with doses of 13, 26 and 52mg/kg, and isovaleryl spiramycin III groups with doses of 13, 26 and 52mg/kg significantly increase compared with that of the control group (P ⁇ 0.05, P ⁇ 0.01).
- the spleen index of the positive drug cyclophosphamide control group is significantly lower than that of the control group (P ⁇ 0.01).
- the spleen index of the mice in the isovaleryl spiramycin I groups with doses of 13, 26 and 52mg/kg, isovaleryl spiramycin II groups with doses of 13, 26 and 52mg/kg, and isovaleryl spiramycin III groups with doses of 13, 26 and 52mg/kg do not change significantly compared with that of the control group. Table 52.
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| AU2019209738A1 (en) * | 2018-01-19 | 2020-09-10 | Shenyang Fuyang Pharmaceutical Technology Co., Ltd. | MTOR inhibitor, pharmaceutical composition and use thereof |
| JP2022540291A (ja) * | 2019-05-16 | 2022-09-15 | 沈陽福洋医薬科技有限公司 | 線維化を予防、緩和及び／又は治療するための薬物、組成製品及びその応用 |
| US11351185B2 (en) | 2020-03-11 | 2022-06-07 | Asclea Corporation | Use of isovalerylspiramycins as anti-cancer agents to inhibit metastasis |
| CN113577086B (zh) * | 2020-04-30 | 2023-05-02 | 沈阳福洋医药科技有限公司 | 异戊酰螺旋霉素类化合物或其组合物在制备治疗免疫失调的药物中的应用 |
| CN113372397A (zh) * | 2021-06-22 | 2021-09-10 | 天方药业有限公司 | 一种己二酸螺旋霉素的制备方法 |
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| GB1540397A (en) * | 1976-12-08 | 1979-02-14 | May & Baker Ltd | Spiramycin esters |
| CA2127578A1 (en) * | 1993-07-08 | 1995-01-09 | Keiichi Ajito | 16-membered macrolide derivatives and process for producing the same |
| US7087237B2 (en) * | 2003-09-19 | 2006-08-08 | Advanced Ocular Systems Limited | Ocular solutions |
| WO2007144876A1 (en) * | 2006-06-12 | 2007-12-21 | Ramot At Tel-Aviv University Ltd. | Methods for treating cancer |
| CN101362784A (zh) * | 2008-10-06 | 2009-02-11 | 山东大学 | 埃博霉素苷类化合物和以其为活性成分的组合物及其应用 |
| CN101773510B (zh) | 2010-03-09 | 2013-06-05 | 沈阳同联集团有限公司 | 异戊酰螺旋霉素iii的分离制备 |
| CN101785778A (zh) * | 2010-03-09 | 2010-07-28 | 沈阳同联集团有限公司 | 异戊酰螺旋霉素i的分离制备及其应用 |
| CN101785779B (zh) | 2010-03-09 | 2014-03-05 | 沈阳同联集团有限公司 | 异戊酰螺旋霉素ii的分离制备 |
| RU2647237C1 (ru) * | 2010-05-25 | 2018-03-14 | Шенянг Фуянг Фармасьютекал Технолоджи Ко.Лтд. | Левоизовалерилспирамицин iii, препараты, способ приготовления и употребления |
| CN102229634B (zh) * | 2010-05-25 | 2014-05-28 | 沈阳同联集团有限公司 | 左旋异戊酰螺旋霉素i、其制剂、制备方法及应用 |
| CN102247396B (zh) * | 2010-05-25 | 2014-05-28 | 沈阳同联集团有限公司 | 左旋可利霉素、其药物组合物、制备方法及应用 |
| US11077126B2 (en) * | 2017-04-06 | 2021-08-03 | Shenyang Fuyang Pharmaceutical Technology Co., Ltd. | Use of carrimycin and pharmaceutically acceptable salts of carrimycin in manufacturing medicament for treating and/or preventing tumor |
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